The present application is directed to radiolabeled cyclic polypeptides, pharmaceutical compositions comprising radiolabeled cyclic polypeptides, and methods of using the radiolabeled cyclic polypeptides. Such polypeptides can be used in imaging studies, such as Positron Emitting Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).
|
##STR00069##
23. A pharmaceutical composition comprising a radiolabeled cyclopeptide selected from the group consisting of:
##STR00073##
and a pharmaceutically acceptable carrier.
26. A method of monitoring the level of integrin αvβ3 or visualizing integrin αvβ3 expression within a body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; and (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; wherein the radiolabeled cyclopeptide is selected from the group consisting of:
##STR00077##
29. A method for imaging of blood vessel growth in solid tumors based on expression of integrin αvβ3 within the body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is selected from the group consisting of:
##STR00081##
##STR00068##
wherein:
R5 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, —(C1-C6 alkylene)-aryl, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl; wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle and heterocycle groups are each optionally substituted;
wherein the chiral centers attached to
m is 0, 1, 2, 3 or 4; and
n is 1, 2, 3, 4 or 5.
##STR00062##
wherein:
R1 is selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are optionally substituted;
wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of positron or gamma emitters; and
X is a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic and sugar moiety.
5. A cyclopeptide of formula ii: e####
##STR00059##
wherein
each R1 is independently selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are each optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 75Br, 124I, 125I and 131I; and
W is
##STR00060##
where p is an integer between 0 and 15;
v is 0, 1, 2, or 3;
m is 0, 1 or 2;
each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are each optionally substituted; and
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted and wherein the configuration of the chiral center that carries the R5 substituent may be R or S or mixtures thereof.
##STR00053##
wherein:
R1 is selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted;
R7 is absent or is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted; wherein R2, R3 and R7 are not all H;
X is a 5 or 6-membered heterocycle or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
Y is a 5 or 6-membered heterocycle, or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
where at least one of X and Y, but not both X and Y is a 5 or 6-membered heterocycle; and
w is 1, 2, 3, 4, or 5;
wherein any one of X, Y, R2, R3, and R7 comprises a radionuclide selected from the group consisting of positron or gamma emitters.
##STR00070##
wherein:
R1 is selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted;
R7 is absent or is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted; wherein R2, R3 and R7 are not all H;
X is a 5 or 6-membered heterocycle or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
Y is a 5 or 6-membered heterocycle, or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
where at least one of X and Y, but not both X and Y is a 5 or 6-membered heterocycle; and
w is 1, 2, 3, 4, or 5;
wherein any one of X, Y, R2, R3, and R7 comprises a radionuclide selected from the group consisting of positron or gamma emitters; and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising a radiolabeled cyclopeptide of formula ii or formula iii:
##STR00071##
wherein:
each R1 is independently selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153 Gd and 32P;
each of X and W is selected from the group consisting of:
##STR00072##
where each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle, and heterocycle, groups are each optionally substituted;
v is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3 or 4; and
p is an integer between 1 and 25;
wherein the configuration of the chiral centers may be R or S or mixtures thereof; and a pharmaceutically acceptable carrier.
24. A method of monitoring the level of integrin αvβ3 or visualizing integrin αvβ3 expression within a body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; and (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; wherein the radiolabeled cyclopeptide is of formula I:
##STR00074##
wherein
R1 is selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted;
R7 is absent or is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted; wherein R2, R3 and R7 are not all H;
X is a 5 or 6-membered heterocycle or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
Y is a 5 or 6-membered heterocycle, or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
where at least one of X and Y, but not both X and Y is a 5 or 6-membered heterocycle; and
w is 1, 2, 3, 4, or 5;
wherein any one of X, Y, R2, R3, and R7 comprises a radionuclide selected from the group consisting of positron or gamma emitters.
27. A method for imaging of blood vessel growth in solid tumors based on expression of integrin αvβ3 within the body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is of formula I:
##STR00078##
wherein
R1 is selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted;
R7 is absent or is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl-(C1-C6 alkylene)-, a 3- to 7-membered carbocycle, and a 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, aryl-alkylene, carbocycle and heterocycle groups are each optionally substituted; wherein R2, R3 and R7 are not all H;
X is a 5 or 6-membered heterocycle or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
Y is a 5 or 6-membered heterocycle, or a linker comprising a hydrophilic moiety selected from the group consisting of hydroxyl, carbonyl, sulfonamide, sulfonate, phosphate, polar amino acid moiety, peg moiety, sugar mimetic, and sugar moiety;
where at least one of X and Y, but not both X and Y is a 5 or 6-membered heterocycle; and
w is 1, 2, 3, 4, or 5;
wherein any one of X, Y, R2, R3, and R7 comprises a radionuclide selected from the group consisting of positron or gamma emitters.
25. A method of monitoring the level of integrin αvβ3 or visualizing integrin αvβ3 expression within a body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; and (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; wherein the radiolabeled cyclopeptide is of formula ii or formula iii:
##STR00075##
wherein
each R1 is independently selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 61Cu, 62Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153Gd and 32P;
each of X and W is selected from the group consisting of:
##STR00076##
where each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle, and heterocycle, groups are each optionally substituted;
wherein the configuration of the chiral centers may be R or S or mixtures thereof;
v is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3 or 4; and
p is an integer between 1 and 25.
28. A method for imaging of blood vessel growth in solid tumors based on expression of integrin αvβ3 within the body of a patient, the method comprising: (a) administering to the patient a radiolabeled cyclopeptide; (b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is of formula ii or formula iii:
##STR00079##
wherein:
each R1 is independently selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153Gd and 32P;
each of X and W is selected from the group consisting of:
##STR00080##
where each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle, and heterocycle, groups are each optionally substituted;
wherein the configuration of the chiral centers may be R or S or mixtures thereof;
v is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3 or 4; and
p is an integer between 1 and 25.
2. The cyclopeptide of
3. The cyclopeptide of
Y is a 5 or 6-membered heterocycle;
X is selected from the group consisting of:
##STR00054##
wherein Z is selected from the group consisting of:
##STR00055##
W is selected from the group consisting of:
##STR00056##
A is selected from the group consisting of:
##STR00057##
each R1 is independently selected from the group consisting of a side chain of a natural amino acid and a side chain of an unnatural amino acid, wherein the natural amino acid and the unnatural amino acid is either in the D or L form;
each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle, and heterocycle, groups are each optionally substituted;
each R6 is independently selected from the group consisting of —H, —OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl-(C1-C6 alkylene)-, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, and aryl-alkylene groups are each optionally substituted;
each v is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3 or 4;
p is an integer between 1 and 110;
q is 1, 2, 3 or 4;
r is 1, 2 or 3;
r′ is 0 or 1;
s is 1, 2, 3 or 4; and
the radionuclide is selected from the group consisting of 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153Gd, 132P;
wherein the configuration of the chiral centers may be R or S or mixtures thereof.
4. The cyclopeptide of
R1 is a side chain of a natural amino acid;
R7 is absent;
X is
##STR00058##
Y is 1,2,3-triazolyl; and
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are each optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 75Br, 124I, 125I and 131I.
6. The cyclopeptide of each R1 is benzyl;
R2 is H;
R3 is an optionally substituted C1-C6 alkyl comprising a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 75Br, 124I, 125I and 131I; and
W is
e####
##STR00061##
where p is 0, 1, 2, 3, 4, or 5.
8. The cyclopeptide of
9. The cyclopeptide of
10. The cyclopeptide of
R1 is a side chain of a natural amino acid; and
X is selected from the group consisting of:
##STR00063##
where each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, 3- to 7-membered carbocycle, 3- to 7-membered heterocycle, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, carbocycle and heterocycle groups are each optionally substituted;
each R6 is independently selected from the group consisting of —H, —OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl-(C1-C6 alkylene)-, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, and aryl-alkylene groups are each optionally substituted;
v is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3 or 4;
p is an integer between 1 and 110;
q is 1, 2, 3 or 4;
r is 1, 2 or 3;
r′ is 0 or 1
s is 1, 2, 3 or 4; and
the radionuclide is selected from the group consisting of 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153Gd and 32P;
where the configuration of the chiral centers may be R or S or mixtures thereof.
##STR00064##
R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are each optionally substituted, wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 75Br, 124I, 125I and 131I;
R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted and wherein the configuration of the chiral center that carries the R5 substituent may be R or S or mixtures thereof; and
m is 0, 1 or 2.
12. The cyclopeptide of
R2 is hydrogen;
R3 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted, wherein R3 comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, and 18F;
R5 is hydrogen; and
m is 0.
13. The cyclopeptide of R2 and R3 are each independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted; wherein R2 and R3 are not both H; and either R2 or R3, or both R2 and R3 comprise a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 75Br, 124I, 125I and 131I;
X is
e####
##STR00065##
where R5 is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted and wherein the configuration of the chiral center that carries the R5 substituent may be R or S or mixtures thereof;
m is 0, 1, or 2; and
p is an integer between 1 and 90.
14. The cyclopeptide of
R2 is hydrogen;
R3 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted, and R3 comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, and 18F;
R5 is hydrogen;
m is 0; and
p is an integer between 1 and 15.
15. The cyclopeptide of X is
e####
##STR00066##
where each R6 is independently selected from the group consisting of —H, —OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkyloxy, hydroxy-C1-C6-alkyl, and C1-C6-alkoxy-C1-C6-alkyl, wherein the alkyl, alkenyl, and alkyloxy groups are each optionally substituted;
q is 2, 3 or 4;
r is 2 or 3;
r′ is 0; and
s is 1 or 2.
16. The cyclopeptide of
X is
e####
##STR00067##
where each R4 is independently selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, aryl, aryl-(C1-C6 alkylene)-, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and a peg moiety, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, carbocycle, and heterocycle groups are each optionally substituted; and v is 1, 2, 3, or 4.
18. The cyclopeptide of
R5 is selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted;
wherein the chiral center in the cyclic peptide is R configured and the chiral center bearing the R5 residue is R or S or mixtures thereof;
m is 0, 1 or 2; and
n is 1, 2, 3 or 4.
19. The cyclopeptide of
R5 is selected from the group consisting of —H, and an optionally substituted C1-C4 alkyl;
m is 0 or 1; and
n is 2, 3 or 4.
|
|||||||||||||||||||||||||||||||||
This application claims priority to U.S. Provisional Application No. 60/844,837, filed Sep. 15, 2006 and to U.S. Provisional Application No. 60/963,272, filed Aug. 3, 2007, the contents of each of which are hereby incorporated in their entirety by reference.
The present application is directed to radiolabeled cyclic polypeptides (cyclopeptides), pharmaceutical compositions comprising radiolabeled cyclic polypeptides, and methods of using the radiolabeled cyclic polypeptides. The present application is further directed to methods of preparing the radiolabeled cyclic polypeptides. Such polypeptides can be used in imaging studies, such as Positron Emitting Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).
In particular this application discloses the preparation and use of radiolabeled cyclopeptide analogs for imaging integrins (e.g., integrin αvβ3) in vivo. Click chemistry is utilized to attach a radiolabel to cyclopeptides that contain an Arg-Gly-Asp (RGD) fragment and that further carry hydrophilic linkages, such as oligo- or poly-ethyleneglycol (“PEG”) moieties, polar amino acid moieties, sugars, or sugar mimetics, such as cyclohexane diols or polyols. One advantage disclosed in the present application is a click chemistry labeling step that is easy to perform, that is fast and provides high yields of radiolabeled products that are easy to purify. The binding affinities of the radiolabeled cyclopeptide analogs for different integrins have been determined using biochemical in vitro assays, such as cell-binding assays or surface plasmon resonance assays. The click chemistry-derived integrin ligands of the present application display surprisingly high binding affinities to the biological target, and demonstrate very favorable pharmacokinetic behavior in mice (e.g. high tumor uptake and fast clearance through predominantly renal routes).
A number of medical diagnostic procedures, including PET and SPECT utilize radiolabeled compounds. PET and SPECT are very sensitive techniques and require small quantities of radiolabeled compounds, called tracers. The labeled compounds are transported, accumulated and converted in vivo in exactly the same way as the corresponding non-radioactively compound. Tracers, or probes, can be radiolabeled with a radionuclide useful for PET imaging, such as 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I and 131I, or with a radionuclide useful for SPECT imaging, such as 99Tc, 75Br, 61Cu, 153Gd, 125I, 131I and 32P.
PET creates images based on the distribution of molecular imaging tracers carrying positron-emitting isotopes in the tissue of the patient. The PET method has the potential to detect malfunction on a cellular level in the investigated tissues or organs. PET has been used in clinical oncology, such as for the imaging of tumors and metastases, and has been used for diagnosis of certain brain diseases, as well as mapping brain and heart function. Similarly, SPECT can be used to complement any gamma imaging study, where a true 3D representation can be helpful, for example, imaging tumor, infection (leukocyte), thyroid, or bones.
Angiogenesis plays a vital role in tumor growth and metastatic spread. Tumor angiogenesis is a multi-step process characterized by chemotactic and mitogenic response of endothelial cells to angiogenic growth factors, proteolytic degradation of extracellular matrix, and modulation of endothelial cell interaction with extracellular matrix mediated by integrin receptors. Each of these steps may represent a potential target for the development of tumor angiogenic and metastatic diagnostics.
Integrins are a family of membrane-spanning adhesion receptors composed of noncovalently linked α and β subunits, which combine to form a variety of heterodimers with different ligand recognition properties. Several integrins have been shown to interact with polypeptide domains containing the Arg-Gly-Asp (“RGD”) amino acid sequence present in various extracellular matrix-associated adhesive glycoproteins. Besides cell adhesion to extracellular matrix, integrins also mediate intracellular events that control cell migration, proliferation, and survival.
One member of the integrin family, αvβ3 integrin, plays a key role in angiogenesis. It interacts with several extracellular matrix proteins, such as vitronectin, fibrinogen, fibronectin, thrombin, and thrombospondin, and cooperates with molecules such as metalloproteases, growth factors, and their receptors. Due to its numerous functions and relatively limited cellular distribution, αvβ3 integrin represents an attractive target for diagnostic and therapeutic intervention. In addition, findings that several extracellular matrix proteins, such as vitronectin, fibrinogen, and thrombospondin interact with integrins via the RGD sequence has lead to the development of synthetic linear and cyclic peptides containing RGD sequence for integrin targeting. See e.g. DE 197 25 368, U.S. Pat. No. 5,849,692, U.S. Pat. No. 6,169,072, U.S. Pat. No. 6,566,491, U.S. Pat. No. 6,610,826, and WO 2005/111064.
It has also been demonstrated in a number of murine tumor models that radiolabeled peptides containing the RGD motif can be used for non-invasive investigation of αVβ3 integrin expression. The development of noninvasive methods to visualize and quantify integrin αvβ3 expression in vivo appears to be closely related to the success of antiangiogenic therapy based on integrin antagonism. Precise documentation of integrin receptor levels allows appropriate selection of patients who will most likely benefit from an anti-integrin treatment regimen. Imaging can also be used to provide an optimal dosage and time course for treatment based on receptor occupancy studies. In addition, imaging integrin expression is used to evaluate anti-integrin treatment efficacy and to develop new therapeutic drugs with favorable tumor targeting and in vivo kinetics.
Kessler and co-workers [1] developed the pentapeptide cyclo(-Arg-Gly-Asp-D-Phe-Val-) (“c(RGDfV)”) which showed high affinity and selectivity for integrin αvβ3. To date, most integrin αvβ3 targeted PET studies have been focused on radiolabeling of c(RGDfV)-based antagonists due to its high binding affinity (nanomolar to subnanomolar range for monomeric and multimeric c(RGDfV) respectively). In the late 1990's, the monomeric peptide c(RGDyV) was labeled by Haubner et al. [2] with 125I. This tracer revealed receptor-specific tumor uptake in vivo. However, the labeled peptide had rapid tumor washout and unfavorable hepatobiliary excretion resulting from its high lipophilicity, which limited its further application. Glycosylation on the lysine side chain of a similar RGD peptide, c(RGDyK), decreased lipophilicity and hepatic uptake [3]. A glycopeptide based on c(RGDfK), [18F]galacto-RGD, was then synthesized:
##STR00001##
It was demonstrated that [18F]galacto-RGD exhibited integrin αvβ3-specific tumor uptake in integrin-positive M21 melanoma xenograft model [4-6, see also 19]. Moreover, [18F]galacto-RGD was sensitive enough for visualization of integrin αvβ3 expression resulting exclusively from the tumor vasculature using an A431 human squamous cell carcinoma model, in which the tumor cells are integrin negative. Initial clinical trials in healthy volunteers and a limited number of cancer patients revealed that this tracer could be safely administered to patients and was able to delineate certain lesions that were integrin-positive with reasonable contrast.
[18F]Galacto-RGD currently represents one promising integrin marker for PET imaging of angiogenesis. As a monomeric RGD peptide tracer, it has relatively low tumor targeting efficacy; clinical use of this tracer is severely limited because of its relatively low integrin binding affinity, modest tumor standard uptake values, and unfavorable pharmacokinetic behavior. Therefore, tumors with low integrin expression level may not be detectable. In addition, prominent activity accumulation in the liver, kidneys, spleen, and intestines was observed in both preclinical models and human studies. As a result, it was difficult to visualize lesions in the abdomen. This tracer is also very difficult to synthesize, thereby limiting its availability.
Conjugation of PEG (poly(ethyleneglycol)) (“PEGylation”) has been shown to improve many properties of peptides and proteins, including plasma stability, immunogenicity, and pharmacokinetics. Chen et al. [7-9] conjugated RGD-containing peptides with PEG moieties of different sizes and synthesized radioiodinated, 18F- and 64Cu-labeled derivatives. PEGylation demonstrated an effect on the pharmacokinetics, tumor uptake and retention of the RGD peptides, which seem to depend strongly on the nature of lead structure and on the size of the PEG moiety. Additional strategies for improving pharmacokinetic behavior as well as tumor uptake and retention pattern of peptides with an RGD motif include introduction of hydrophilic amino acids and multimerisation of RGD.
Applicants observed that despite a few good examples of RGD-containing tracers, several key challenges remain to be resolved. Firstly, the pharmacokinetic behavior of the tracer needs to be improved. Although glycosylation improved the pharmacokinetic behavior of a number of tracers to a certain degree, prominent activity accumulation in the liver, kidneys, spleen, and intestines is still observed in both preclinical models and human studies, which makes it difficult to visualize lesions in the abdomen. Secondly, a major drawback of the strategies examined by others is that the radiolabeling process is very difficult to perform, which limits the exploration of improved derivatives and the use of these imaging agents as standard clinical biomarkers.
The present application discloses effective imaging agents developed for detecting blood vessel growth in tumors (angiogenesis) in vivo. In the labeled cyclopeptides of the present application, RGD-containing cyclic peptides carry polar residues on a pendant amino acid side chain; those polar residues are coupled with a moiety comprising a radionuclide via a ‘click chemistry’ linkage (i.e. a 1,4- or 1,5-disubstituted 1,2,3-triazole). These click chemistry-derived compounds are easy to both synthesize and radiolabel. The compounds demonstrate surprisingly high binding affinity to integrin αvβ3, and improved pharmacokinetic properties compared to cyclic polypeptides belonging to the same class. The imaging agents disclosed in the present application are used as a marker for imaging integrins in vivo. More specifically, this application discloses a means for detecting blood vessel growth in certain cancers in vivo, as well as a means for monitoring the efficacy of cancer therapy. Since the imaging agent allows in vivo imaging of blood vessel growth in solid tumors, it enables personalized anti-angiogenesis cancer therapies.
To solve the problem of low signal to noise ratios, a library of potential integrin markers using the RGD sequence as a binding motif have been prepared. The library, assembled using click chemistry, was screened for binding to integrins. Those compounds that displayed high binding affinities were selected for radiolabeling with positron-emitting isotopes or conjugation with appropriate linker moieties and radioactive isotopes such as [18F]-fluorine for in vivo PET imaging. Applicants' approach of using click chemistry enabled rapid synthesis and testing of many different potential integrin ligands as candidate PET tracers.
The embodiments of the invention and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments and examples that are described and/or illustrated in the accompanying drawings and detailed in the following description. It should be noted that the features of one embodiment may be employed with other embodiments as the skilled artisan would recognize, even if not explicitly stated herein. The examples used herein are intended merely to facilitate an understanding of ways in which the invention may be practiced and to further enable those of skill in the art to practice the embodiments of the present application. Accordingly, the examples and embodiments herein should not be construed as limiting the scope of the application, which is defined solely by the appended claims.
Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic and peptide synthesis and pharmaceutical sciences.
An “alkyl” group is a straight, branched, saturated or unsaturated, aliphatic group having a chain of carbon atoms, optionally with oxygen, nitrogen or sulfur atoms inserted between the carbon atoms in the chain or as indicated. Alkyl groups may be optionally substituted. A (C1-C6)alkyl, for example, includes alkyl groups that have a chain of between 1 and 6 carbon atoms, and include, for example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, and the like. An alkyl group, such as a “C1-C6 alkyl,” that forms a part of a group or linker is a divalent alkyl group, and also may be referred to as an “alkylene” group. Similarly, an alkenyl group, alkynyl group, aryl group, etc in a structure that is shown as a divalent group may be referred to as an alkenylenyl, alkynylenyl, arylenyl group respectively.
An alkyl as noted with another group such as an aryl group, represented as “arylalkyl” for example, is intended to be a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group (as in (C1-C6)alkyl, for example) and/or aryl group or when no atoms are indicated means a bond between the aryl and the alkyl group. Nonexclusive examples of such group include benzyl, phenylethyl and the like.
An “alkylene” group or “alkylenyl group” is a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group; for example, a —(C1-C3)alkylene- or —(C1-C3)alkylenyl-.
The term “alkenyl” refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkene groups may be optionally substituted. Exemplary groups include 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl.
The term “alkynyl” refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkyne groups may be optionally substituted. Exemplary groups include 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl and ethynyl.
The term “carbocycle” (or carbocyclyl) as used herein refers to a C3 to C8 monocyclic, saturated, partially saturated or aromatic ring. Bonds in a carbocycle depicted as “———” indicate bonds that can be either single or double bonds. Carbocycles may be optionally substituted. Non-exclusive examples of carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, benzyl, naphthene, anthracene, phenanthracene, biphenyl and pyrene.
A “heterocycle” is a carbocycle group wherein one or more of the atoms forming the ring is a heteroatom that is a N, O, or S. The heterocycle may be saturated, partially saturated or aromatic. Bonds in a heterocycle depicted as “———” indicate bonds that can be either single or double bonds. Heterocycles may be optionally substituted. Non-exclusive examples of heterocyclyl (or heterocycle) include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, 1,4-diazaperhydroepinyl, acetonidyl-4-one, 1,3-dioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyranyl and the like.
The term “alkoxy” or “alkyloxy” includes linear or branched alkyl groups that are attached to divalent oxygen. The alkyl group is as defined above. Examples of such substituents include methoxy, ethoxy, t-butoxy, and the like. The term “alkoxyalkyl” refers to an alkyl group that is substituted with one or more alkoxy groups. Alkoxy groups may be optionally substituted. The term “aryloxy” refers to an aryl group that is attached to an oxygen, such as phenyl-O—, etc.
The term “optionally substituted” or “substituted” refers to the specific group wherein one to four hydrogen atoms in the group may be replaced by one to four substituents, independently selected from alkyl, aryl, alkylene-aryl, hydroxy, alkoxy, aryloxy, perhaloalkoxy, heterocycle, azido, amino, guanidino, amidino, halo, alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaminoalkyl, alkoxyaryl, arylamino, phosphono, sulfonyl, carboxamidoaryl, hydroxyalkyl, haloalkyl, cyano, alkoxyalkyl, and perhaloalkyl. In addition, the term “optionally substituted” or “substituted” in reference to R2 or R3 includes groups substituted by one to four substituents, as identified above, that further comprise a positron or gamma emitter. Such positron emitters include, but are not limited to, 11C, 13N, 15O, 18F, 61Cu, 62Cu, 64Cu, 67Cu, 68Ga, 124I, 125I, 131I, 99Tc, 75Br, 153Gd and 32P.
As used herein, the term “side chain” of a natural or unnatural amino acid refers to “Q” group in the amino acid formula, as exemplify with NH2CH(Q)CO2H.
As used herein, the term “polar amino acid moiety” refers to the side chain, Q, of a polar natural or unnatural amino acid. Polar natural amino acids include but are not limited to arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine and lysine.
As used herein, “natural amino acid” refers to the naturally occurring amino acids: glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine and lysine.
The term “unnatural amino acid” refers to any derivative of a natural amino acid including for example D and L forms, and α- and β-amino acid derivatives. It is noted that certain amino acids, e.g., hydroxyproline, that are classified as a non-natural amino acid herein, may be found in nature within a certain organism or a particular protein. The following non-exclusive examples of non-natural amino acids and amino acid derivatives may be used according to the application (common abbreviations in parentheses): β-alanine (β-ALA), γ-aminobutyric acid (GABA), ornithine, 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), γ-carboxyglutamic acid, 2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta), aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), para-aminophenylalanine (4-NH2-Phe), biphenylalanine (Bip), para-bromophenylalanine (4-Br-Phe), ortho-chlorophenylalanine] (2-Cl-Phe), meta-chlorophenylalanine (3-Cl-Phe), para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine (3-Cl-Tyr), para-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-Cl2-Phe), 3,4-difluororphenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), ortho-fluorophenylalanine (2-F-Phe), meta-fluorophenylalanine (3-F-Phe), para-fluorophenylalanine (4-F-Phe), meta-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), 5-hydroxytryptophan (5-OH-Trp), hydroxyproline (Hyp), para-iodophenylalanine (4-I-Phe), 3-iodotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), isonipecotic acid (Inp), meta-methyltyrosine (3-Me-Tyr), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), para-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), norleucine (Nle), norvaline (Nva), ornithine (Orn), ortho-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine, and thiazolidine-4-carboxylic acid (thioproline, Th). Additionally, N-alkylated amino acids may be used, as well as amino acids having amine-containing side chains (such as Lys and Orn) in which the amine has been acylated or alkylated.
As used herein, “sugar moiety” refers to an oxidized, reduced or substituted saccharide monoradical or diradical covalently attached via any atom(s) of the sugar moiety. Representative sugars include, by way of illustration, hexoses such as D-glucose, D-mannose, D-xylose, D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine, daunosamine, 3-epi-daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine, D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, sialyic acid, iduronic acid, L-fucose, and the like; pentoses such as D-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose; disaccharides such as 2-O-(α-L-vancosaminyl)-β-D-glucopyranose, 2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose, or maltose; derivatives such as acetals, amines, acylated, sulfated and phosphorylated sugars; and oligosaccharides having from 2 to 10 sugar units.
As used herein, a hexose structure that is represented below, for example:
##STR00002##
showing the curved lines is intended to represent a structure having the stereochemistry of any one of the natural sugars, including allose, altrose, galactose, glucose, gulose, idose, mannose, talose, etc. . . . , as well as their unnatural and synthetic hexose analogs and derivatives, and also includes certain sugar moieties.
As used herein, “sugar mimetic” refers to carbocycles or heterocycles substituted with at least one hydroxyl group. Such carbocycle groups include, but are not limited to cyclohexane, cyclohexene, cyclopentane and cyclobutane; such heterocycles include, but are not limited to, pyrrolidine and piperidine.
As used herein, “PEG moiety” refers to a fragment of poly (ethylene glycol), a polymer of ethylene oxide. PEG has the formula:
##STR00003##
where m′ is an integer between 1 and 200, alternatively between 1 and 110 or between 10 and 90; m′ can also be an integer between 50 and 75. Alternately m′ can be an integer between 1 and 50 or even between 1 and 15.
“Linker” as used herein refers to a chain comprising 1 to 200 atoms and may comprise atoms or groups, such as C, —NR—, O, S, —S(O)—, —S(O)2—, CO, —C(NR)—, a PEG moiety, and the like, and wherein R is H or is selected from the group consisting of (C1-10)alkyl, (C3-8)cycloalkyl, aryl(C1-5)alkyl, heteroaryl(C1-5)alkyl, amino, aryl, heteroaryl, hydroxy, (C1-10)alkoxy, aryloxy, heteroaryloxy, each substituted or unsubstituted. The linker chain may also comprise part of a saturated, unsaturated or aromatic ring, including monocyclic (e.g. a 1,5-cyclohexylenyl group, sugar mimetic, and sugar moiety), polycyclic and heteroaromatic rings (e.g. a 2,4-pyridinyl group etc. . . . ). The representation of “(C1-3)alkyl”, for example, is used interchangeably with “C1-C3alkyl” to mean the same. As used herein, the term “linker” may be used to link interconnecting moieties such as —X—YR2R3, including linking a cyclic polypeptide moiety and a triazole moiety.
As used herein, where a divalent group, such as a linker, is represented by a structure -A-B—, as shown below, it is intended to also represent a group that may be attached in both possible permutations, as noted in the two structures below.
While there are metabolites of the tracer found in the mouse body, the percentage of the original tracer and that of the metabolites can be calculated from the radio-HPLC data.
The data show that in each example only minor amounts radioactive metabolites were found in the murine tissue and fluid samples. Thus, Compound 7 and Compound 10 are each very stable in a mouse body. See e.g.
All references cited herein are incorporated by reference as if each had been individually incorporated by reference in its entirety. In describing embodiments of the present application, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. Nothing in this specification should be considered as limiting the scope of the present invention. All examples presented are representative and non-limiting. The above-described embodiments may be modified or varied, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.
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Chen, Kai, Kolb, Hartmuth C., Walsh, Joseph C., Karimi, Farhad, Liang, Qianwa, Padgett, Henry Clifton
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